WO2011075634A1 - Dérivés bicycliques utiles comme inhibiteurs de dpp-1 - Google Patents

Dérivés bicycliques utiles comme inhibiteurs de dpp-1 Download PDF

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WO2011075634A1
WO2011075634A1 PCT/US2010/060986 US2010060986W WO2011075634A1 WO 2011075634 A1 WO2011075634 A1 WO 2011075634A1 US 2010060986 W US2010060986 W US 2010060986W WO 2011075634 A1 WO2011075634 A1 WO 2011075634A1
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carbonyl
amino
group
phenyl
compound
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PCT/US2010/060986
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English (en)
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Edward C. Lawson
Shyamali Ghosh
Renee L. Desjarlais
Dennis J. Hlasta
Carsten Schubert
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Janssen Pharmaceutica Nv
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Priority to AU2010330792A priority Critical patent/AU2010330792B2/en
Priority to CN201080064075.6A priority patent/CN102753524B/zh
Priority to ES10798434.6T priority patent/ES2573698T3/es
Priority to EP10798434.6A priority patent/EP2513054B1/fr
Priority to JP2012544881A priority patent/JP5908410B2/ja
Publication of WO2011075634A1 publication Critical patent/WO2011075634A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/32—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention is directed to novel bicyclic derivatives, pharmaceutical compositions containing them and their use in the treatment of disorders and conditions modulated by DPP-1 .
  • COPD Chronic Obstructive Pulmonary Disease
  • Granzymes A & B are the neutral serine proteases that are expressed exclusively in the granules of activated cytotoxic T lymphocytes.
  • PMN polymorphonuclear neutrophil
  • MMPs matrix metalloproteases
  • Dipeptidyl Peptidase-1 (DPP-1 , cathepsin C) is a member of the lysosomal papain-type cysteine protease family that also includes cathepsin B, K, H, L, O, and S.
  • DPP-1 (MW 200kd) is composed of a dimer of disulfide- linked heavy and light chains, both from a single protein precursor.
  • DPP-1 mRNA is highly expressed in tissues such as lung, spleen, kidney and liver; in inflammatory cells such as PMN, cytotoxic T lymphocytes, alveolar macrophages and mast cells.
  • the biological function of DPP-1 is to convert inactive proenzymes into active enzyme by removing a dipeptide from N- terminal.
  • the proenzymes that are activated by DPP-1 are PMN-derived proteases, granzymes A & B, chymase and tryptase. Since these enzymes play an important pathological role in COPD, inhibition of DDP-1 by small molecules would be a rational therapeutic intervention for COPD. Additional therapeutic indications for a DPP-1 inhibitor are asthma, rhinitis, and rheumatoid arthritis.
  • DPP-1 DPP-1 mediated disorders and conditions, including but not limited to rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, sepsis, irritable bowel disease, cystic fibrosis, and abdominal aortic aneurism.
  • R 1 is selected from the group consisting of Ci -4 alkyl, -C(0)-NH 2 , C3- 6 cycloalkyl, phenyl and 5 to 6 membered heteroaryl; wherein the heteroaryl is optionally substituted with one or more substituents independently selected from halogen and Ci -4 alkyl;
  • n is an integer from 0 to 1 ;
  • L is selected from the group consisting of — CH2CH2-
  • R is selected from the group consisting of hydrogen, methyl and ethyl; (and wherein the L substituent group is incorporated into the compound of formula (I) as drawn; more particularly, the L substituent group is incorporated into the compound of formula (I) such that the N atom of the L substituent group is bound to the C(O) of the compound of formula (I))
  • Y is selected from the group consisting of N and CH;
  • X is selected from the group consisting of N(R B ), O and S; wherein R B is selected from the group consisting of hydrogen and Ci -4 alkyl;
  • R 2 is selected from the group consisting of hydrogen, halogen, nitro, - C0 2 H, -C(0)-NR c R D , -Q, -O-Q and -C(0)-NH-Q;
  • R c and R D are each independently selected from the group consisting of hydrogen and Ci -4 alkyl; alternatively, R c and R D are taken together with the nitrogen atom to which they are bound to form a ring structure selected from the group consisting of piperidin-1 -yl, piperazin-1 -yl, pyrrolidin-1 - yl, morpholin-4-yl, 1 ,2,3,4-tetrahydroquinolin-1 -yl and 1 ,2,3,4-tetrahydro- isoquinolin-2-yl;
  • Q is selected from the group consisting of aryl, aralkyl, heterocyclyl, benzo[d][1 ,3]dioxolyl and 2,3-dihydro-benzo[b][1 ,4]dioxinyl;
  • aryl or heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, C -4 alkyl, halogenated Ci -4 alkyl, Ci -4 alkoxy, halogenated Ci -4 alkoxy, -C0 2 H, -C(0)-NR E R F , -S0 2 - NR E R F and phenyl; wherein R E and R F are each independently selected from the group consisting of hydrogen and Ci -4 alkyl;
  • heterocyclyl contains one or more S heteroatoms
  • said heterocyclyl may be further optionally substituted on said one or more S heteroatoms with one to two oxo groups
  • R 1 is selected from the group consisting of Ci- alkyl, -C(0)-NH 2 , C 3 - 6 cycloalkyl, phenyl and 5 to 6 membered heteroaryl; wherein the heteroaryl is optionally substituted with one or more substituents independently selected from halogen and Ci -4 alkyl;
  • n is an integer from 0 to 1 ;
  • L is selected from the group consisting of -CH 2 CH 2 -NR A - and - CH 2 CH 2 CH 2 -NR A -; wherein R A is selected from the group consisting of hydrogen, methyl and ethyl; (and wherein the L substituent group is
  • the L substituent group is incorporated into the compound of formula (I) such that the N atom of the L substituent group is bound to the C(O) of the compound of formula (I))
  • X is selected from the group consisting of N(R B ), O and S; wherein R B is selected from the group consisting of hydrogen and Ci -4 alkyl;
  • R 2 is selected from the group consisting of hydrogen, halogen, nitro, -
  • R c and R D are each independently selected from the group consisting of hydrogen and Ci -4 alkyl; alternatively, R c and R D are taken together with the nitrogen atom to which they are bound to form a ring structure selected from the group consisting of piperidin-1 -yl, piperazin-1 -yl, pyrrolidin-1 - yl, morpholin-4-yl, 1 ,2,3,4-tetrahydroquinolin-1 -yl and 1 ,2,3,4-tetrahydro- isoquinolin-2-yl;
  • Q is selected from the group consisting of aryl, aralkyl, heterocyclyl, benzo[d][1 ,3]dioxolyl and 2,3-dihydro-benzo[b][1 ,4]dioxinyl;
  • aryl or heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, C -4 alkyl, halogenated Ci -4 alkyl, Ci -4 alkoxy, halogenated Ci -4 alkoxy, -C0 2 H, -C(0)-NR E R F , -S0 2 - NR E R F and phenyl; wherein R E and R F are each independently selected from the group consisting of hydrogen and Ci -4 alkyl;
  • heterocyclyl contains one or more S heteroatoms
  • said heterocyclyl may be further optionally substituted on said one or more S heteroatoms with one to two oxo groups; and pharmaceutically acceptable salts thereof.
  • the present invention is further directed to processes for the preparation of the compounds of formula (I) and / or the compounds of formula (II).
  • the present invention is further directed to a product prepared according to the process described herein.
  • Illustrative of the invention is a pharmaceutical composition comprising a pharmaceutically acceptable carrier and the product prepared according to the process described herein.
  • An illustration of the invention is a pharmaceutical composition made by mixing the product prepared according to the process described herein and a pharmaceutically acceptable carrier.
  • Illustrating the invention is a process for making a pharmaceutical composition comprising mixing the product prepared according to the process described herein and a pharmaceutically acceptable carrier.
  • Exemplifying the invention are methods of treating a disorder mediated by DPP-1 (cathepsin C) (e.g., a disorder selected from the group consisting of rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, sepsis, irritable bowel disease, cystic fibrosis, and abdominal aortic aneurism) in a subject in need thereof comprising administering to the subject a disorder mediated by DPP-1 (cathepsin C) (e.g., a disorder selected from the group consisting of rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, sepsis, irritable bowel disease, cystic fibrosis, and abdominal aortic aneurism) in a subject in need thereof comprising administering to the subject a disorder mediated by DPP-1 (cathepsin C) (e.g., a disorder selected from the group consisting of rheumatoid arthritis, asthma,
  • Another example of the invention is the use of any of the compounds described herein in the preparation of a medicament for treating: (a) rheumatoid arthritis, (b) asthma, (c) chronic obstructive pulmonary disease, (d) sepsis, (e) irritable bowel disease, (f) cystic fibrosis, or (g) abdominal aortic aneurism, in a subject in need thereof.
  • the present invention is directed to a compound as described herein for use in a methods for treating a disorder selected from the group consisting of rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, sepsis, irritable bowel disease, cystic fibrosis, and abdominal aortic aneurism, in a subject in need thereof.
  • a disorder selected from the group consisting of rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, sepsis, irritable bowel disease, cystic fibrosis, and abdominal aortic aneurism
  • the present invention is directed to compounds of formula (I)
  • the compounds of formula (I) and formula (I I) of the present invention are inhibitors of DPP-1 , useful in the treatment of disorders, diseases and conditions mediated by DPP-1 (cathepsin C), including, but not limited to, rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, sepsis, irritable bowel disease, cystic fibrosis, and abdominal aortic aneurism.
  • R 1 is selected from the group consisting of Ci- alkyl, -C(0)-NH 2 , C 3 - 6 cycloalkyl and 5 to 6 membered heteroaryl; wherein the 5 to 6 membered heteroaryl is optionally substituted with one to two substituent selected from the group consisting of halogen and Ci -4 alkyl.
  • R 1 is selected from the group consisting of Ci- alkyl, -C(0)-NH 2 , C -6 cycloalkyl and 5 to 6 membered heteroaryl; wherein the 5 to 6 membered heteroaryl is optionally substituted with a substituent selected from the group consisting of halogen and Ci -4 alkyl.
  • R 1 is selected from the group consisting of ethyl, cyclobutyl, thien-2-yl, thien-3-yl, 2-bromo-thien-2-yl, 5-chloro-thien-2-yl, thiazol-2-yl, 4-methyl-thiazol-2-yl, pyrazol-1 -yl, fur-2-yl, 1 - methyl-imidazol-4-yl and amino-carbonyl.
  • R 1 is selected from the group consisting of ethyl, thien-2-yl, thiazol-2-yl, fur-2-yl and 1 -methyl-imidazol-4-yl.
  • R 1 is selected from the group consisting of ethyl, thien-2-yl, thiazol-2-yl and fur-2-yl. In another embodiment of the present invention, R 1 is selected from the group consisting of ethyl, thien-2-yl and thiazol-2-yl. In another embodiment of the present invention, R 1 is thien-2-yl.
  • R 1 is Ci -4 alkyl. In another embodiment of the present invention, R 1 is Ci- 2 alkyl. In another embodiment of the present invention, R 1 is ethyl.
  • n is 0. In another embodiment of the present invention, n is 1.
  • L is
  • L is selected from the group consisting of -CH 2 CH 2 -N(R A )- and -CH 2 CH 2 CH 2 -N(R A )-; wherein R A is selected from the group consisting of hydrogen, methyl and ethyl.
  • L is -CH 2 CH 2 CH 2 -N(R A )-; wherein R A is selected from the group consisting of hydrogen, methyl and ethyl.
  • L is -CH 2 CH 2 -NR A -.
  • L is -CH 2 CH 2 CH 2 -NR A -.
  • L is -CH 2 CH 2 CH 2 -NH-.
  • L is selected from the group consisting of -CH 2 CH 2 -N(R A )- and -CH 2 CH 2 CH 2 -N(R A )-; wherein R A is selected from the group consisting of hydrogen, methyl and ethyl.
  • L is -CH 2 CH 2 -NR A -.
  • L is
  • R A is selected from the group consisting of hydrogen, methyl and ethyl.
  • L is selected from the group
  • L is selected from the group consisting of -CH 2 CH 2 -NH-, -CH 2 CH 2 CH 2 -NH- and -CH 2 CH 2 CH 2 - N(CH 2 CH 3 )-.
  • L is selected from the group consisting of -CH 2 CH 2 -NH-, -CH 2 CH 2 CH 2 -NH- and -CH 2 CH 2 CH 2 - N(CH 2 CH 3 )-.
  • L is selected
  • R is selected from the group consisting of hydrogen, methyl and ethyl. In another embodiment of the present invention, R is hydrogen.
  • indolyl is selected from the group consisting of indolyl, 1 -methyl-indolyl, benzofuryl, benzothienyl and benzimidazolyl.
  • Y is selected from the group consisting of N and CH; and X is selected from the group consisting of N(R B ), O and S; provided that when X is O or S, then Y is CH.
  • Y is N. In another embodiment of the present invention, Y is CH. In an embodiment of the present invention X is O. In another embodiment of the present invention, X is S. In another embodiment of the present invention, X is NR .
  • R B is selected from the group consisting of hydrogen, methyl, ethyl, isopropyl and t-butyl. In another embodiment of the present invention, R B is selected from the group consisting of hydrogen, methyl and ethyl. In another embodiment of the present invention, R B is selected from the group consisting of hydrogen and methyl. In another embodiment of the present invention, R B is hydrogen.
  • Y is selected from the group consisting of N and CH; and X is selected from the group consisting of N(R B ), O and S; wherein R B is selected from the group consisting of hydrogen and d- 2 alkyl.
  • Y is selected from the group consisting of CH and N; and X is selected from the group consisting of NH, N(CH 3 ) and O; provided that when X is O, then Y is CH.
  • Y is selected from the group consisting of CH and N; and X is selected from the group consisting of NH and O; provided that when X is O, then Y is CH.
  • Y is CH; and X is NH.
  • X is selected from the group consisting of N(R B ) and
  • R B is selected from the group consisting of hydrogen and
  • X is selected from the group consisting of S and NH.
  • R 2 is selected from the group consisting of hydrogen, halogen, nitro, -C0 2 H, -C(0)-NR c R D , phenyl, -O- phenyl, heterocyclyl, and -C(0)-NH-Q; wherein R c and R D are each
  • R c and R D are taken together with the nitrogen atom to which they are bound to form a ring structure selected from the group consisting of piperidin-1 -yl, pyrrolidin-1 -yl, 1 ,2,3,4-tetrahydroquinolin-1 -yl and 1 ,2,3,4- tetrahydro-isoquinolin-2-yl; wherein Q is selected from the group consisting of aryl, aralkyl, heterocyclyl, benzo[d][1 ,3]dioxolyl and 2,3-dihydro-benzo[b][1 ,4]dioxinyl;
  • aryl or heterocyclyl is optionally substituted with one to two substituents independently selected from the group consisting of halogen, cyano, C -4 alkyl, fluorinated d- 4 alkyl, Ci -4 alkoxy, fluorinated Ci -4 alkoxy, -C0 2 H, -C(0)NR E R F , -S0 2 -NR E R F and phenyl; wherein R E and R F are each independently selected from the group consisting of hydrogen and Ci -2 alkyl; and wherein the heterocyclyl contains one or more S heteroatoms, said heterocyclyl may be further optionally substituted on said one or more S heteroatoms with one to two oxo groups.
  • R 2 is selected from the group consisting of hydrogen, halogen, nitro, carboxy, phenyl, -O-phenyl, - C(0)-NR c R D and -C(0)-NH-Q; wherein R c and R D are each independently selected from the group consisting of hydrogen and Ci -2 alkyl; alternatively, R c and R D are taken together with the nitrogen atom to which they are bound to form a ring structure selected from the group consisting of 1 ,2,3,4- tetrahydroquinolin-1 -yl and 1 ,2,3,4-tetrahydro-isoquinolin-2-yl;
  • Q is selected from the group consisting of phenyl, naphthyl, -C-
  • R 2 is selected from the group consisting of hydrogen, 5-bromo, 5-(carboxy), 5-(nitro), 5-(phenyl), 5-(4- fluorophenyl), 5-(4-methoxy-phenyl), 5-(3,4-dimethoxy-phenyl), 5-(3,5- dimethoxy-phenyl), 5-(3-cyano-phenyl), 5-(3-carboxy-phenyl), 5-(4-carboxy- phenyl), 5-(4-trifluoromethyl-phenyl), 5-(4-trifluoromethoxy-phenyl), 5-(3,5- di(trifluoromethyl)-phenyl), 5-(2-(aminocarbonyl)-phenyl), 5-(3-(aminocarbonyl)- phenyl), 5-(4-(aminocarbonyl)-phenyl), 5-(3-(aminosulfonyl)-phenyl), 5- (phenoxy), 5-(3,4-d
  • R 2 is selected from the group consisting of hydrogen, 5-bromo, 5-(phenyl), 5-(4-fluorophenyl), 5-(4- methoxy-phenyl), 5-(3,4-dimethoxy-phenyl), 5-(3,5-dimethoxy-phenyl), 5-(3- cyano-phenyl), 5-(3-carboxy-phenyl), 5-(4-carboxy-phenyl), 5-(4-trifluoromethyl- phenyl), 5-(4-trifluoromethoxy-phenyl), 5-(3,5-di(trifluoromethyl)-phenyl), 5-(2- (aminocarbonyl)-phenyl), 5-(3-(aminocarbonyl)-phenyl), 5-(4-(aminocarbonyl)- phenyl), 5-(3-(aminosulfonyl)-phenyl), 5-(phenoxy), 5-(3,4-dimethoxy-phenoxy), 5-(2- (aminocarbon
  • R 2 is selected from the group consisting of 5-bromo, 5-(phenyl), 5-(4-fluorophenyl), 5-(4-methoxy- phenyl), 5-(3,4-dimethoxy-phenyl), 5-(3,5-dimethoxy-phenyl), 5-(3-cyano- phenyl), 5-(3-carboxy-phenyl), 5-(4-carboxy-phenyl), 5-(4-trifluoromethyl- phenyl), 5-(4-trifluoromethoxy-phenyl), 5-(3,5-di(trifluoromethyl)-phenyl), 5-(3- (aminocarbonyl)-phenyl), 5-(4-(aminocarbonyl)-phenyl), 5-(3-(aminosulfonyl)- phenyl), 5-(phenoxy), 5-(3,4-dimethoxy-phenoxy), 5-(3-chlorophenyl-amino- carbonyl
  • R 2 is selected from the group consisting of 5-(4-methoxy-phenyl), 5-(3,4-dimethoxy-phenyl), 5-(3,5- dimethoxy-phenyl), 5-(3-cyano-phenyl), 5-(4-carboxy-phenyl), 5-(3- (aminocarbonyl)-phenyl), 5-(phenoxy), 5-(3,4-dimethoxy-phenoxy), 5-(3- methoxyphenyl-amino-carbonyl), 5-(4-methoxyphenyl-amino-carbonyl), 5-(2,6- dimethylphenyl-amino-carbonyl), 5-(3,4-dimethoxyphenyl-amino-carbonyl), 5- (quinolin-3-yl-amino-carbonyl), 5-(quinolin-5-yl-amino-carbonyl), 5-(quinolin-6- yl-amino-carbonyl), 5-(isoquinol
  • R 2 is selected from the group consisting of 5-(3,4-dimethoxyphenyl) and 5-(3,4-dimethoxyphenyl- amino-carbonyl). In another embodiment of the present invention, R 2 is hydrogen.
  • the R 2 group is bound at the
  • the R group is bound at the 5- or 6- position of the core. In another embodiment, the R 2 group is bound at the 5-
  • the present invention is directed to compounds of formula (I) wherein the stereo-center denoted with the "*" symbol is present in (R) configuration.
  • the compound of formula (I) is present in the (R) configurations in an enantiomeric excess of greater than or equal to about 80%, more preferably, at an enantiomeric excess of greater than or equal to about 90%, more preferably still, at an enantiomeric excess of greater than or equal to about 95%, more preferably still, at an enantiomeric excess of greater than or equal to about 98%, most preferably, at an enantiomeric excess of greater than or equal to about 99%.
  • the present invention is directed to compounds of formula (I) wherein the stereo-center denoted with the "*" symbol is present in (S) configuration.
  • the compound of formula (I) is present in the (S) configurations in an enantiomeric excess of greater than or equal to about 80%, more preferably, at an enantiomeric excess of greater than or equal to about 90%, more preferably still, at an enantiomeric excess of greater than or equal to about 95%, more preferably still, at an enantiomeric excess of greater than or equal to about 98%, most preferably, at an enantiomeric excess of greater than or equal to about 99%.
  • the present invention is directed to compounds of formula (II) wherein the stereo-center denoted with the "*" symbol is present in (R) configuration.
  • the compound of formula (II) is present in the (R) configurations in an enantiomeric excess of greater than or equal to about 80%, more preferably, at an enantiomeric excess of greater than or equal to about 90%, more preferably still, at an enantiomeric excess of greater than or equal to about 95%, more preferably still, at an enantiomeric excess of greater than or equal to about 98%, most preferably, at an enantiomeric excess of greater than or equal to about 99%.
  • the present invention is directed to compounds of formula (II) wherein the stereo-center denoted with the "*" symbol is present in (S) configuration.
  • the compound of formula (II) is present in the (S) configurations in an enantiomeric excess of greater than or equal to about 80%, more preferably, at an enantiomeric excess of greater than or equal to about 90%, more preferably still, at an enantiomeric excess of greater than or equal to about 95%, more preferably still, at an enantiomeric excess of greater than or equal to about 98%, most preferably, at an enantiomeric excess of greater than or equal to about 99%.
  • the present invention is directed to compounds of formula (I) whose IC 5 o, measured according to the procedure described in Biological Example 1 , is less than or equal to about 10 ⁇ , preferably less than or equal to about 5.0 ⁇ , more preferably less than or equal to about 1 .0 ⁇ , more preferably less than or equal to about 0.5 ⁇ , more preferably less than or equal to about 0.1 ⁇ .
  • the present invention is directed to compounds of formula (II) whose IC 5 o, measured according to the procedure described in Biological Example 1 , is less than or equal to about 10 ⁇ , preferably less than or equal to about 5.0 ⁇ , preferably less than or equal to about 1 .0 ⁇ , more preferably less than or equal to about 0.5 ⁇ , more preferably less than or equal to about 0.1 ⁇ .
  • halogen shall mean chlorine, bromine, fluorine and iodine.
  • alkyl whether used alone or as part of a substituent group, shall include straight and branched carbon chain
  • alkyl radicals include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, and the like.
  • C X . Y wherein X and Y are integers, when used with alkyl shall mean a carbon chain composition of between X and Y carbon atoms.
  • the term "Ci -4 alkyl” shall mean a straight or branched carbon chain composition of 1 to 4 carbon atoms.
  • alkyl and "-(C-i- 4 alkyl)-” shall denote any alkyl or Ci -4 alkyl carbon chain as herein defined, wherein said alkyl or Ci -4 alkyl chain is divalent and is further bound through two points of attachment, preferably through two terminal carbon atoms.
  • halogenated d. 4 alkyl shall mean any Ci -4 alkyl group as defined above substituted with at least one halogen atom, preferably substituted with a least one fluoro atom. Suitable examples include but are not limited to -CF 3 , -CCI 3 , -CH 2 -CF 3 , - CH 2 CCI 3 , -CF 2 -CF 2 -CF 2 -CF 3 , and the like.
  • fluorinated Ci -4 alkyl shall mean any Ci -4 alkyl group as defined above substituted with at least one fluoro atom.
  • Suitable examples include but are not limited to -CF 3 , -CH 2 -CF 3 , -CF 2 -CF 2 -CF 2 -CF 3 , and the like.
  • the halogenated or fluorinated alkyl is -CF 3 .
  • alkoxy whether used alone or as part of a substituent group, shall denote an oxygen ether radical of any of the above described straight and branched carbon chain compositions of one to six carbon atoms.
  • alkoxy radicals include methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t-butoxy, n-pentoxy, and the like.
  • C x-Y wherein X and Y are integers, when used with alkoxy shall mean an oxygen radical of any of the above described carbon chain
  • C-i- 4 alkoxy shall mean an oxygen ether radical of any straight or branched carbon chain composition of 1 to 4 carbon atoms.
  • examples include methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and t-butoxy.
  • halogenated d. 4 alkoxy shall mean any Ci -4 alkoxy group as defined above substituted with at least one halogen atom, preferably substituted with a least one fluoro atom.
  • Suitable examples include but are not limited to -OCF 3 , -OCCI3, -OCH2-CF3, - OCH 2 CCI 3 , -OCF 2 -CF 2 -CF 2 -CF 3 , and the like.
  • fluorinated Ci -4 alkoxy shall mean any Ci -4 alkoxy group as defined above substituted with at least one fluoro atom.
  • Suitable examples include but are not limited to -OCF 3 , -OCH 2 -CF 3 , -OCF 2 -CF 2 -CF 2 - CF 3 , and the like.
  • the halogenated or fluorinated alkoxy is -OCF 3 .
  • aryl shall refer to unsubstituted carbocylic aromatic groups such as phenyl, naphthyl, and the like.
  • aralkyl shall mean any Ci -4 alkyl group substituted with an aryl group such as phenyl, naphthyl and the like. For example, benzyl, phenylethyl-, phenyl-n-propyl-, naphth-1 -ylmethyl-, and the like.
  • C 3 - 6 cycloalkyl shall mean any stable 3-6 membered monocyclic, saturated ring system, for example cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • 5 to 6 membered heteroaryl shall denote any five or six membered monocyclic aromatic ring structure containing at least one heteroatom selected from the group consisting of O, N and S, optionally containing one to three additional heteroatoms independently selected from the group consisting of O, N and S.
  • the heteroaryl group may be attached at any heteroatom or carbon atom of the ring such that the result is a stable structure.
  • heteroaryl groups include, but are not limited to, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, imidazolyl, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl, and the like.
  • Preferred heteroaryl groups include, but are not limited to, thienyl, thiazolyl, pyrazolyl, imidazolyl, pyridyl and triazolyl.
  • heterocyclyl shall denote any five to seven membered monocyclic, saturated, partially unsaturated or aromatic ring structure containing at least one heteroatom selected from the group consisting of O, N and S, optionally containing one to three additional heteroatoms independently selected from the group consisting of O, N and S; or any nine to ten membered saturated, partially unsaturated, partially aromatic (including benzo-fused) or aromatic bicyclic ring system containing at least one heteroatom selected from the group consisting of O, N and S, optionally containing one to four additional heteroatoms independently selected from the group consisting of O, N and S.
  • the heterocyclyl group may be attached at any heteroatom or carbon atom of the ring such that the result is a stable structure.
  • suitable heterocyclyl groups include, but are not limited to, thienyl, thiazolyl, pyrazolyl, imidazolyl, pyridyl, triazolyl, quinolinyl, isoquinolinyl, benzothiazolyl, benzimidazolyl, benzothiophenyl, 1 H-pyrazolo[3,4-d]pyrimidinyl, pyrrolinyl, pyrrolidinyl, dioxalanyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, piperidinyl, dioxanyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl, indolinyl, chromenyl, 3,4-methylenedioxyphen
  • Preferred heterocyclyl groups include, but are not limited to, thienyl, thiazolyl, pyrazolyl, imidazolyl, pyridyl, triazolyl, quinolinyl, isoquinolinyl, benzothiazolyl, benzimidazolyl, benzothiophenyl, piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, 1 H- pyrazolo[3,4-d]pyrimidinyl, 1 ,2,3,4-tetrahydro-quinolinyl and 1 ,2,3,4-tetrahydro- isoquinolinyl.
  • substituents preferably from one to five substituents, more preferably from one to three substituents, most preferably from one to two substituents,
  • the enantiomer is present at an enantiomeric excess of greater than or equal to about 80%, more preferably, at an enantiomeric excess of greater than or equal to about 90%, more preferably still, at an enantiomeric excess of greater than or equal to about 95%, more preferably still, at an enantiomeric excess of greater than or equal to about 98%, most preferably, at an enantiomeric excess of greater than or equal to about 99%.
  • the diastereomer is present at an diastereomenc excess of greater than or equal to about 80%, more preferably, at an diastereomenc excess of greater than or equal to about 90%, more preferably still, at an diastereomeric excess of greater than or equal to about 95%, more preferably still, at an diastereomeric excess of greater than or equal to about 98%, most preferably, at an diastereomeric excess of greater than or equal to about 99%.
  • crystalline forms for the compounds of the present invention may exist as polymorphs and as such are intended to be included in the present invention.
  • some of the compounds of the present invention may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are also intended to be encompassed within the scope of this invention.
  • phenylCr C 6 alkylaminocarbonylCi-C 6 alkyl refers to a group of the formula
  • Pd(PPh 3 ) 2 CI 2 Bis(triphenylphosphine)palladium (II) chloride
  • TMS Trimethylsilyl
  • isolated form shall mean that the compound is present in a form which is separate from any solid mixture with another compound(s), solvent system or biological environment.
  • the compound of formula (I) is prepared as an isolated form.
  • the compound of formula (II) is prepared as an isolated form.
  • the term “substantially pure compound” shall mean that the mole percent of impurities in the isolated compound is less than about 5 mole percent, preferably less than about 2 mole percent, more preferably, less than about 0.5 mole percent, most preferably, less than about 0.1 mole percent.
  • (I) is present as a substantially pure compound.
  • the compound of formula (II) is present as a substantially pure compound.
  • the term "substantially free of a corresponding salt form(s)" when used to described the compound of formula (I) shall mean that mole percent of the corresponding salt form(s) in the isolated base of formula (I) is less than about 5 mole percent, preferably less than about 2 mole percent, more preferably, less than about 0.5 mole percent, most preferably less than about 0.1 mole percent.
  • the compound of formula (I) is present in a form which is substantially free of corresponding salt form(s).
  • the compound of formula (I) is present in a form which is substantially free of corresponding salt form(s).
  • treatment shall include the management and care of a subject or patient (preferably mammal, more preferably human) for the purpose of combating a disease, condition, or disorder and includes the administration of a compound of the present invention to prevent the onset of the symptoms or complications, alleviate the symptoms or complications, or eliminate the disease, condition, or disorder.
  • prevention shall include (a) reduction in the frequency of one or more symptoms; (b) reduction in the severity of one or more symptoms; (c) the delay or avoidance of the development of additional symptoms; and / or (d) delay or avoidance of the development of the disorder or condition.
  • a subject in need of thereof shall include any subject or patient (preferably a mammal, more preferably a human) who has experienced or exhibited at least one symptom of the disorder, disease or condition to be prevented.
  • a subject in need thereof may additionally be a subject (preferably a mammal, more preferably a human) who has not exhibited any symptoms of the disorder, disease or condition to be prevented, but who has been deemed by a physician, clinician or other medical profession to be at risk of developing said disorder, disease or condition.
  • the subject may be deemed at risk of developing a disorder, disease or condition (and therefore in need of prevention or preventive treatment) as a consequence of the subject's medical history, including, but not limited to, family history, pre-disposition, co-existing (comorbid) disorders or conditions, genetic testing, and the like.
  • subject refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment. Preferably, the subject has experienced and / or exhibited at least one symptom of the disease or disorder to be treated and / or prevented.
  • terapéuticaally effective amount means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease or disorder being treated.
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts.
  • DPP-1 mediated disorder shall include any condition, disease or disorder which may be mediated through inhibition of DPP-1 activity.
  • disorders mediated by DPP-1 include, but are not limited to
  • disorders of the respiratory tract including obstructive diseases of the airways including asthma, including bronchial, allergic, intrinsic, extrinsic, exercise-induced, drug induce (including aspirin and NSAID-induced) and dust induced asthma, both intermittent and persistent and of all severities, and other causes of airway hyper-responsiveness; chronic obstructive pulmonary disease (COPD); bronchitis, including infectious and eosinophilic bronchitis;
  • COPD chronic obstructive pulmonary disease
  • emphysema bronchiectasis
  • cystic fibrosis a fibrosis
  • sacroidosis a fibrosis
  • farmer's lung and related diseases hypersensitive pnemonitis
  • lung fibrosis including cryptogenic fibrosing alveolitis, idiopathic interstitial pneumonias, fibrosis complicating antineoplastic therapy and chronic infection, including tuberculosis and
  • aspergillosis and other fungal infections complications of lung transplantation; vascullitic and thrombotic disorders of the lung vasculature, and pulmonary hypertension; antitussive activity including treatment of chronic cough associated with inflammatory and secretory conditions of the airways, and iatrogenic cough; acute and chronic rhinitis including rhinitis medicamentosa, and vasomotor rhinitis; perennial and seasonal allergic rhinitis including rhinitis nervosa (hay fever); nasal polyposis; acute viral infection including the common cold, and infection due to respiratory syncytial virus, influenza, coronavirus (including SARS) and adenovirus;
  • eye disorders blepharitis, conjunctivitis, including perennial and vernal allergic conjunctivitis; LTDis; anterior and posterior uveitis; choroiditis; autoimmune, degenerative or inflammatory disorders affecting the retina;
  • opthalmitis including sympathetic opthalmitis; sarcoidosis; infections including viral, fugal and bacterial;
  • glomerulnephritis glomerulnephritis
  • nephritic syndrome cystitis including acute and chronic
  • cystitis and Hunner's ulcer (interstitial) cystitis and Hunner's ulcer; acute and chronic urethritis, prostatitis, epididymitis, oophoritis and salpingitis; vulvo-vaginitis; Peyronie's disease; erectile dysfunction;
  • allograft rejection disorders acute and chronic following, for example, transplantation of kidney, heart, liver, lung, bone marrow, skin or cornea or following blood transfusion; or chronic graft versus host disease;
  • cancers including treatment of common cancers including prostate, breast, lung, ovarian, pancreatic, bowel and colon, stomach, skin and brain tumors and malignancies affecting the bone marrow (including leukaemias) and lymphoproliferative systems, such as Hodgkin's and non-Hodgkin's lymphoma; including the prevention and treatment of metastatic disease and tumor recurrences, and paraneoplstic syndrome; and (h) infectious diseases: viral diseases such as genital warts, common warts, plantar warts, hepatitis B, hepatitis C, herpes simplex virus, molluscum contagiosum, variola, human immunodeficiency virus (HIV), human papilloma virus (HPV), cytomegalovirus (CMV), varicella zoser virus (VZV), rhinovirus, adenovirus, coronavirus, influenza, para-influenza; bacterial diseases such
  • the present invention is directed to methods for the treatment and / or prevention of a DDP-1 mediated disorder; wherein the DPP-1 mediated disorder is selected from the group consisting of chronic obstructive pulmonary disease (COPD), asthma, acute lung injury, adult respiratory distress syndrome, abdominal or thoracic aneurism, rheumatoid arthritis, osteoarthritis, multiple sclerosis, sepsis and taxoplasmosis.
  • COPD chronic obstructive pulmonary disease
  • the present invention is directed to methods for the treatment and / or prevention of a DDP-1 mediated disorder; wherein the DPP-1 mediated disorder is selected from the group consisting of rheumatoid arthritis, asthma, chronic obstructive pulmonary disease (COPD), sepsis, irritable bowel disease, cystic fibrosis, and abdominal aortic aneurism.
  • DPP-1 mediated disorder is selected from the group consisting of rheumatoid arthritis, asthma, chronic obstructive pulmonary disease (COPD), sepsis, irritable bowel disease, cystic fibrosis, and abdominal aortic aneurism.
  • reaction step(s) is performed under suitable conditions, according to known methods, to provide the desired product.
  • a reagent or reagent class/type e.g. base, solvent, etc.
  • the individual reagents are independently selected for each reaction step and may be the same of different from each other.
  • the organic or inorganic base selected for the first step may be the same or different than the organic or inorganic base of the second step.
  • reaction step of the present invention may be carried out in a variety of solvents or solvent systems, said reaction step may also be carried out in a mixture of the suitable solvents or solvent systems.
  • aprotic solvent shall mean any solvent that does not yield a proton. Suitable examples include, but are not limited to DMF, 1 ,4-dioxane, THF, acetonitrile, pyridine, dichloroethane, dichloromethane, MTBE, toluene, acetone, and the like.
  • leaving group shall mean a charged or uncharged atom or group which departs during a
  • nitrogen protecting group shall mean a group which may be attached to a nitrogen atom to protect said nitrogen atom from participating in a reaction and which may be readily removed following the reaction.
  • Other suitable nitrogen protecting groups may be found in texts such as T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991 .
  • oxygen protecting group shall mean a group which may be attached to an oxygen atom to protect said oxygen atom from participating in a reaction and which may be readily removed following the reaction.
  • Suitable oxygen protecting groups include, but are not limited to, acetyl, benzoyl, t-butyl-dimethylsilyl, trimethylsilyl (TMS), MOM, THP, and the like.
  • TMS trimethylsilyl
  • Other suitable oxygen protecting groups may be found in texts such as T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991 .
  • reaction step of the present invention may be carried out in a variety of solvents or solvent systems, said reaction step may also be carried out in a mixture of the suitable solvents or solvent systems.
  • the processes for the preparation of the compounds according to the invention give rise to mixture of stereoisomers
  • these isomers may be separated by conventional techniques such as preparative chromatography.
  • the compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution.
  • the compounds may, for example, be resolved into their component enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation with an optically active acid, such as (-)-di-p-toluoyl-D-tartaric acid and/or (+)-di-p-toluoyl-L-tartaric acid followed by fractional crystallization and regeneration of the free base.
  • the compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, the compounds may be resolved using a chiral HPLC column.
  • chiral HPLC against a standard may be used to determine percent enantiomeric excess (%ee).
  • the enantiomeric excess may be calculated as follows
  • any of the processes for preparation of the compounds of the present invention it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991 .
  • the protecting groups may be removed at a convenient subsequent stage using methods known from the art.
  • the salts of the compounds of this invention refer to non-toxic "pharmaceutically acceptable salts.”
  • Other salts may, however, be useful in the preparation of compounds according to this invention or of their pharmaceutically acceptable salts.
  • Suitable pharmaceutically acceptable salts of the compounds include acid addition salts which may, for example, be formed by mixing a solution of the compound with a solution of a
  • suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g., sodium or potassium salts; alkaline earth metal salts, e.g., calcium or magnesium salts; and salts formed with suitable organic ligands, e.g., quaternary ammonium salts.
  • representative pharmaceutically acceptable salts include, but are not limited to, the following: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride,
  • acids which may be used in the preparation of pharmaceutically acceptable salts include, but are not limited to, the following: acids including acetic acid, 2,2-dichloroacetic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, (+)-camphoric acid, camphorsulfonic acid, (+)- (1 S)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1 ,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid, D-glucoronic
  • bases which may be used in the preparation of pharmaceutically acceptable salts include, but are not limited to, the following: bases including ammonia, L-arginine, benethamine, benzathine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2-(diethylamino)- ethanol, ethanolamine, ethylenediamine, N-methyl-glucamine, hydrabamine, 1 H-imidazole, L-lysine, magnesium hydroxide, 4-(2-hydroxyethyl)-morpholine, piperazine, potassium hydroxide, 1 -(2-hydroxyethyl)-pyrrolidine, secondary amine, sodium hydroxide, triethanolamine, tromethamine and zinc hydroxide.
  • bases including ammonia, L-arginine, benethamine, benzathine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2-(diethylamino)- ethanol,
  • the present invention includes within its scope prodrugs of the compounds of this invention.
  • prodrugs will be functional derivatives of the compounds which are readily convertible in vivo into the required compound.
  • the term “administering” shall encompass the treatment of the various disorders described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to the patient.
  • Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.
  • a suitably substituted compound of formula (V), wherein LG 1 is a suitably selected leaving group such as bromo, chloro, iodo, and the like, preferably bromo, a known compound or compound prepared by known methods, is reacted with a suitably substituted boronic acid, a compound of formula (VI), a known compound or compound prepared by known methods, in the presence of a suitably selected catalysts such as Pd(PPh 3 ) 2 CI 2 ,
  • the compound of formula (VII) is reacted with a suitably substituted compound of formula (VII I), wherein PG 1 is a suitably selected nitrogen protecting group such as BOC, CBz, and the like, a known compound or compound prepared by known methods; in the presence of a suitably selected coupling agent such as HBTU, HATU, HOBt in combination with EDC, and the like; in the presence of a suitably selected organic base such as TEA, DIPEA, pyridine, and the like; optionally in the presence of a catalyst such as DMAP, and the like; in a suitably selected organic solvent such as DMF, DCM, NMP, and the like; to yield the corresponding compound of formula (X).
  • PG 1 is a suitably selected nitrogen protecting group such as BOC, CBz, and the like, a known compound or compound prepared by known methods
  • a suitably selected coupling agent such as HBTU, HATU, HOBt in combination with EDC, and the like
  • a suitably substituted compound of formula (V) wherein LG 1 is a suitably selected leaving group such as bromo, chloro, iodo, and the like, preferably bromo, a known compound or compound prepared by known methods is reacted with a suitably substituted compound of formula (VIII), wherein PG 1 is a suitably selected nitrogen protecting group such as BOC, CBz, and the like, a known compound or compound prepared by known methods; in the presence of a suitably selected coupling agent such as HBTU, HATU, HOBt in combination with EDC, and the like; in the presence of a suitably selected organic base such as TEA, DIPEA, pyridine, and the like; optionally in the presence of a catalyst such as DMAP, and the like; in a suitably selected organic solvent such as DMF, DCM, NMP, and the like; to yield the corresponding compound of formula (IX).
  • LG 1 is a suitably selected leaving group such as bromo, chloro,
  • the compound of formula (IX) is reacted with a suitably substituted boronic acid, a compound of formula (VI), a known compound or compound prepared by known methods, in the presence of a suitably selected catalysts such as Pd(PPh 3 ) 2 CI 2 , Pd(OAc) 2 CI 2 , Pd(dppf)CI 2 , Pd(dppp)CI 2 , and the like; in the presence of a suitably selected base such as Na 2 C0 3 , K 2 C0 3 , Cs 2 C0 3 , and the like; in a suitably selected aprotic solvent such as 1 ,4-dioxane, DMF, toluene, and the like; to yield the corresponding compound of formula (X).
  • a suitably selected catalysts such as Pd(PPh 3 ) 2 CI 2 , Pd(OAc) 2 CI 2 , Pd(dppf)CI 2 , Pd(dppp)CI 2 ,
  • the compound of formula (X) is de-protected according to known methods, to yield the corresponding compound of formula (la).
  • the compound of formula (X) may be de-protected by reacting with a suitably selected acid such as HCI, TFA, and the like; in a suitably selected solvent such DCM, diethyl ether, and the like.
  • a suitably substituted compound of formula (XI), a known compound or compound prepared by known methods is reacted with a suitably substituted compound of formula (VIII), wherein PG 1 is a suitably selected nitrogen protecting group such as BOC, CBz, and the like, a known compound or compound prepared by known methods; in the presence of a suitably selected coupling agent such as HBTU, HATU, HOBt in combination with EDC, and the like; in the presence of a suitably selected organic base such as TEA, DIPEA, pyridine, and the like; optionally in the presence of a catalyst such as DMAP, and the like; in a suitably selected organic solvent such as DMF, DCM, NMP, and the like; to yield the corresponding compound of formula (XII).
  • a suitably selected coupling agent such as HBTU, HATU, HOBt in combination with EDC, and the like
  • organic base such as TEA, DIPEA, pyridine, and the like
  • the compound of formula (XII) is de-protected according to known methods, to yield the corresponding compound of formula (lb).
  • the compound of formula (XII) may be de-protected by reacting with a suitably selected acid such as HCI, TFA, and the like; in a suitably selected solvent such DCM, diethyl ether, and the like.
  • a suitably selected acid such as HCI, TFA, and the like
  • a suitably selected solvent such DCM, diethyl ether, and the like.
  • 3-NH- may be prepared according to the process outlined in Scheme 3, below.
  • a known compound or compound prepared by known methods is reacted with a compound of formula (XII I), a known compound or compound prepared by known methods; in the presence of a suitably selected coupling agent such as HBTU, HATU, HOBt in combination with EDC, and the like; in the presence of a suitably selected organic base such as TEA, DIPEA, pyridine, and the like; optionally in the presence of a catalyst such as DMAP, and the like; in a suitably selected organic solvent such as DMF, DCM, NMP, and the like; to yield the corresponding compound of formula (XIV).
  • a suitably selected coupling agent such as HBTU, HATU, HOBt in combination with EDC, and the like
  • a suitably selected organic base such as TEA, DIPEA, pyridine, and the like
  • a catalyst such as DMAP, and the like
  • organic solvent such as DMF, DCM, NMP, and the like
  • the compound of formula (XIV) is reacted with a suitably substituted compound of formula (XV), wherein LG 2 is a suitably selected leaving group such as iodo, bromo, chloro, and the like, a known compound or compound prepared by known methods, in the presence of a suitably selected palladium catalysts such as Pd(PPh 3 ) , PdCI 2 (PPh 3 ) 2 , Pd(PhCN) 2 CI 2 , and the like; in the presence of Cul; in a suitably selected solvent such as diethylamine, DMF, and the like; to yield the corresponding compound of formula (XVI).
  • LG 2 is a suitably selected leaving group such as iodo, bromo, chloro, and the like
  • a suitably selected palladium catalysts such as Pd(PPh 3 ) , PdCI 2 (PPh 3 ) 2 , Pd(PhCN) 2 CI 2 , and the like
  • Cul in
  • the compound of formula (XVI) is reacted under ring closure conditions, more particularly in the presence of a suitably selected catalyst such as Pd(PhCN) 2 CI 2 , Pd(PPh 3 ) , PdCI 2 (PPh 3 ) 2 , and the like; in a suitably selected solvent such as DMF, diethylamine, and the like; to yield the corresponding compound of formula (XVII).
  • a suitably selected catalyst such as Pd(PhCN) 2 CI 2 , Pd(PPh 3 ) , PdCI 2 (PPh 3 ) 2 , and the like
  • a suitably selected solvent such as DMF, diethylamine, and the like
  • the compound of formula (XVII) is optionally reacted with a suitably selected alkylating agent, a compound of the formula (XVIII); in the presence of a suitably selected base such as NaH, and the like; in a suitably selected solvent such as DMF, THF, diethyl ether, and the like; to yield the
  • the compound of formula (XVII) or the compound of formula (XIX) is de- protected to remove the PG 1 group according to known methods, to yield the corresponding compound of formula (lc).
  • PG 1 is -C(O)- CF 3
  • the compound of formula (XVII) or compound of formula (XVIII) is reacted with a suitably selected base such as NaOH, KOH, and the like; in a suitably selected solvent such as THF, methanol, and the like; to yield the
  • compounds of formula (I) wherein R 2 is -C(0)-NR c R D or -C(0)-NH-Q may be prepared from the corresponding compound of formula (I) wherein R 2 is -C(0)OH by reacting with a suitably substituted amine (a compound of formula NHR C R D or NH2-Q), a known compound or compound prepared by known methods, in the presence of a coupling agent such as BOP-CI, HATU, and the like; in the presence of a suitably selected base such as TEA, DIPEA, and the like; in a suitably selected organic solvent such as DCM, acetonitrile, THF, and the like.
  • a suitably substituted amine a compound of formula NHR C R D or NH2-Q
  • a coupling agent such as BOP-CI, HATU, and the like
  • a suitably selected base such as TEA, DIPEA, and the like
  • organic solvent such as DCM, acetonitrile, THF, and
  • a suitably substituted compound of formula (XV), wherein LG2 is a suitably selected leaving group such as iodo, bromo, chloro, and the like, a known compound or compound prepared by known methods is reacted with a compound of formula (XX), wherein PG 2 is a suitably selected nitrogen protecting group such as BOC, CBz, -C(0)CF 3 , and the like, a known compound or compound prepared by known methods (for example by protecting the compound of formula (XIII), according to known methods); in the presence of a suitably selected palladium catalysts such as Pd(PPh 3 ) 4 , PdCI 2 (PPh 3 )2, Pd(PhCN) 2 CI 2 , and the like; in the presence of Cul; in a suitably selected solvent such as diethylamine, DMF, and the like; to yield the corresponding compound of formula (XXI).
  • LG2 is a suitably selected leaving group such as iodo, bromo, chloro
  • the compound of formula (XXI) is reacted under ring closure conditions, more particularly in the presence of a suitably selected catalyst such as Pd(PhCN) 2 CI 2 , Pd(PPh 3 ) , PdCI 2 (PPh 3 ) 2 , and the like; in a suitably selected solvent such as DMF, diethylamine, and the like; to yield the corresponding compound of formula (XXII).
  • a suitably selected catalyst such as Pd(PhCN) 2 CI 2 , Pd(PPh 3 ) , PdCI 2 (PPh 3 ) 2 , and the like
  • a suitably selected solvent such as DMF, diethylamine, and the like
  • the compound of formula (XXII) is de-protected according to known methods, to yield the corresponding compound of formula (XXIII).
  • PG 2 is BOC
  • the compound of formula (XXII) is de-protected by reacting with a suitably selected acid such as HCI, TFA, and the like, in a suitably selected organic solvent such as DCM, 1 ,4-dioxane, and the like.
  • the compound of formula (XXIII) is reacted with a suitably substituted compound of formula (VII I), wherein PG 1 is a suitably selected nitrogen protecting group such as BOC, CBz, -C(0)CF 3 , and the like, a known compound or compound prepared by known methods; in the presence of a suitably selected coupling agent such as HBTU, HATU, HOBt in combination with EDC, and the like; in the presence of a suitably selected organic base such as TEA, DIPEA, pyridine, and the like; optionally in the presence of a catalyst such as DMAP, and the like; in a suitably selected organic solvent such as DMF, DCM, NMP, and the like; to yield the corresponding compound of formula (XXIV).
  • PG 1 is a suitably selected nitrogen protecting group such as BOC, CBz, -C(0)CF 3 , and the like, a known compound or compound prepared by known methods
  • a suitably selected coupling agent such as HBTU,
  • the compound of formula (XXIV) is de-protected according to known methods, to yield the corresponding compound of formula (Id).
  • PG 1 is BOC
  • the compound of formula (XXIV) is de-protected by reacting with a suitably selected acid such as HCI, TFA, and the like, in a suitably selected organic solvent such as DCM, 1 ,4-dioxane, and the like.
  • W is hydrogen, a known compound or compound prepared by known methods, for the compound of formula (XIII) in Scheme 3, above; or by selecting and substituting a suitably substituted compound of formula (XXV), wherein W is a nitrogen protecting group such as BOC, CBz, -C(0)CF 3 , and the like, a known compound or compound prepared by known methods, for the compound of formula (XX) in Scheme 4 above.
  • the compound of formula (CI) is reacted with a suitably substituted compound of formula (CM), wherein LG 3 is a suitably selected leaving group such as bromo, chloro, iodo, and the like; in the presence of a suitably selected palladium catalyst such as Pd(OAc) 2 , Pd(PPh 3 ) , PdCI 2 (PPh 3 ) 2 , and the like; in the presence of a suitably selected phosphorous agent such as P(o-tolyl) 3 , PPh 3 , and the like; in the presence of a suitably selected base such as TEA, DIPEA, pyridine, and the like; in a suitably selected organic solvent such as acetonitrile, DMF, toluene, and the like; to yield the corresponding compound of formula (Clll).
  • CM suitably substituted compound of formula (CM)
  • LG 3 is a suitably selected leaving group such as bromo, chloro, iodo,
  • the compound of formula (Cl ll) is reacted with a source of hydrogen, such as hydrogen gas in the presence of a suitably selected catalyst such as Pd/C; in a suitably selected organic solvent such as methanol, ethanol, and the like, to yield the corresponding compound of formula (I la).
  • a source of hydrogen such as hydrogen gas
  • a suitably selected catalyst such as Pd/C
  • a suitably selected organic solvent such as methanol, ethanol, and the like
  • PG° is a suitably selected nitrogen protecting groups, for the compound of formula (C); and reacting as described above, to yield the corresponding com ound of formula (lib)
  • PG 4 is a suitably selected nitrogen protecting group such as BOC, CBz, -C(0)CF 3 , and the like, for the compound of formula (CM), and reacted as described above, to yield the corresponding compound of formula (CVI)
  • the compound of formula (CVI) is then de-protected sequentially or Itaneously, according to known methods, and then further optionally substituted by reacting with a suitably substituted alkylating agent, to yield the corresponding compound of formula (I la).
  • the present invention further comprises pharmaceutical compositions containing one or more compounds of formula (I) and / or one or more compounds of formula (II) with a pharmaceutically acceptable carrier.
  • compositions containing one or more of the compounds of the invention described herein as the active ingredient can be prepared by intimately mixing the compound or compounds with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.
  • the carrier may take a wide variety of forms depending upon the desired route of administration (e.g., oral, parenteral).
  • suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, stabilizers, coloring agents and the like;
  • suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like.
  • Solid oral preparations may also be coated with substances such as sugars or be enteric-coated so as to modulate major site of absorption.
  • the carrier will usually consist of sterile water and other ingredients may be added to increase solubility or preservation.
  • injectable suspensions or solutions may also be prepared utilizing aqueous carriers along with appropriate additives.
  • one or more compounds of the present invention as the active ingredient is intimately admixed with a pharmaceutical carrier according to conventional
  • suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like;
  • suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like.
  • tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed.
  • tablets may be sugar coated or enteric coated by standard techniques.
  • the carrier will usually comprise sterile water, through other ingredients, for example, for purposes such as aiding solubility or for preservation, may be included.
  • injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents and the like may be employed.
  • the pharmaceutical compositions herein will contain, per dosage unit, e.g., tablet, capsule, powder, injection, teaspoonful and the like, an amount of the active ingredient necessary to deliver an effective dose as described above.
  • compositions herein will contain, per unit dosage unit, e.g., tablet, capsule, powder, injection, suppository, teaspoonful and the like, of from about 0.01 to about 1 ,000 mg or any amount or range therein, and may be given at a dosage of from about 0.01 mg/kg/day to about 100 mg/kg/day, or any amount or range therein.
  • the dosages may be varied depending upon the requirement of the patients, the severity of the condition being treated and the compound being employed. The use of either daily administration or post-periodic dosing may be employed.
  • compositions are in unit dosage forms from such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, autoinjector devices or suppositories; for oral parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation.
  • the composition may be presented in a form suitable for once-weekly or once- monthly administration; for example, an insoluble salt of the active compound, such as the decanoate salt, may be adapted to provide a depot preparation for intramuscular injection.
  • a pharmaceutical carrier e.g.
  • a solid preformulation composition containing a homogeneous mixture of a compound of the present invention, or a pharmaceutically acceptable salt thereof.
  • preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective dosage forms such as tablets, pills and capsules.
  • This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from 0.01 to about 1 ,000 mg of the active ingredient of the present invention.
  • the tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action.
  • the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
  • the two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release.
  • enteric layers or coatings such materials including a number of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.
  • liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include, aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavoured emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles.
  • Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin.
  • the methods of treating described in the present invention may also be carried out using a pharmaceutical composition
  • a pharmaceutical composition comprising any of the compounds as defined herein and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition may contain between about 0.01 mg and about 1 ,000 mg of the compound, or any amount or range therein; preferably about 1.0 to about 500 mg of the compound, or any amount or range therein, and may be constituted into any form suitable for the mode of administration selected.
  • Carriers include necessary and inert pharmaceutical excipients, including, but not limited to, binders, suspending agents, lubricants, flavorants, sweeteners, preservatives, dyes, and coatings.
  • compositions suitable for oral administration include solid forms, such as pills, tablets, caplets, capsules (each including immediate release, timed release and sustained release formulations), granules, and powders, and liquid forms, such as solutions, syrups, elixers, emulsions, and suspensions.
  • forms useful for parenteral administration include sterile solutions, emulsions and suspensions.
  • compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily.
  • compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal skin patches well known to those of ordinary skill in that art.
  • the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
  • the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like.
  • suitable binders include, without limitation, starch, gelatin, natural sugars such as glucose or beta- lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.
  • Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.
  • liquid forms in suitably flavored suspending or dispersing agents such as the synthetic and natural gums, for example, tragacanth, acacia, methyl- cellulose and the like.
  • suspending or dispersing agents such as the synthetic and natural gums, for example, tragacanth, acacia, methyl- cellulose and the like.
  • sterile suspensions and solutions are desired.
  • Isotonic preparations which generally contain suitable preservatives are employed when intravenous administration is desired.
  • a pharmaceutical carrier which carrier may take a wide variety of forms depending of the form of preparation desired for administration (e.g. oral or parenteral).
  • Suitable pharmaceutically acceptable carriers are well known in the art. Descriptions of some of these pharmaceutically acceptable carriers may be found in The Handbook of Pharmaceutical Excipients, published by the American
  • Compounds of this invention may be administered in any of the foregoing compositions and according to dosage regimens established in the art whenever treatment of disorders mediated by DPP-1 is required.
  • the daily dosage of the products may be varied over a wide range from
  • compositions are preferably provided in the form of tablets containing about 0.01 , 0.05, 0.1 , 0.5, 1 .0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150, 200, 250, 500 and 1 ,000 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated.
  • An effective amount of the drug is ordinarily supplied at a dosage level of from about 0.01 mg/kg to about 100 mg/kg of body weight per day, or any amount or range therein.
  • the range is from about 0.1 mg/kg to about 50.0 mg/kg of body weight per day, or any amount or range therein.
  • the compounds may be administered on a regimen of 1 to 4 times per day.
  • Optimal dosages to be administered may be readily determined by those skilled in the art, and will vary with the particular compound used, the mode of administration, the strength of the preparation, the mode of administration, and the advancement of the disease condition. In addition, factors associated with the particular patient being treated, including patient age, weight, diet and time of administration, will result in the need to adjust dosages.
  • synthesis products are listed as having been isolated as a residue. It will be understood by one of ordinary skill in the art that the term “residue” does not limit the physical state in which the product was isolated and may include, for example, a solid, an oil, a foam, a gum, a syrup, and the like.
  • Triethylamine (10.6 mL, 0.076 mol) and pent-4-yn-1 -amine (2.7 g, 0.033 mol) were added and the resulting mixture was stirred at room temperature for 22 h. The resulting mixture was concentrated in vacuo and the residue purified via flash silica gel
  • STEP B 4-Amino-3-[5-(2-(S)-tert-butoxycarbonylamino-butyrylamino)-pent-1 - ynyll-benzoic acid methyl ester
  • STEP B (S)-2-(3-(2-aminobutanamido)propyl)-N-(3,4-dimethoxyphenyl)-1 H- indole-5-carboxamide
  • STEP F (S)-2-amino-1 -(4-(5-(3,4-dimethoxyphenyl)-1 H-indol-2-yl)piperidin-1 - yl)-3-(thiophen-2-yl)propan-1 -one
  • a 500 mL round bottom flask was charged with methyl 4-amino-3- iodobenzoate (10.0 g, 36.1 mmol), methanol (270 mL), water (30 mL), and lithium hydroxide (1 .82 g, 43.3 mmol).
  • the vessel was flushed with nitrogen, fit with a reflux condenser, and the mixture heated to a gentle reflux for 20 h.
  • the resulting mixture was then cooled to room temperature, acidify with 2N hydrochloric acid, then concentrated in vacuo.
  • a 500 mL round bottom flask was charged with the resulting solid (9.5 g, 36.7 mmol) and dichloromethane (180 mL) was added.
  • Triethylamine (0.77 ml_, 0.55 mmol) and 2-(1 H- benzo[d]imidazol-2-yl)ethanamine (388.2 mg, 1 .66 mmol) were added and the resulting mixture stirred at room temperature for 22 h.
  • the resulting mixture was then concentrated in vacuo and the residue purified via flash silica gel chromatography (ISCO, SF25-40 g column, gradient 90:10 - 75:25
  • Benzotriazole-1 -yl-N,N,N'N'-tetramethyluronium hexafluorophosphate (1025.0 mg, 2.73 mmol) and dimethylformamide (7.0 mL).
  • Triethylamine (1 .17 mL, 8.39 mmol) and 5-bromo-2-piperidin-4-yl-1 H-benzoimidazole hydrochloride salt (730.0 mg, 2.306 mmol) were added and the resulting mixture stirred at room temperature for 22 h.
  • STEP B (2-(4-r5-(3,4-Dimethoxy-phenyl)-1 H-benzoimidazol-2-yll-piperidin-1 - yl)-2-oxo-1 -thiophen-2-ylmethyl-ethyl)-(S)-carbamic acid tert-butyl ester
  • STEP B (1 -[5-(2-Amino-5-bromo-phenyl)-pent-4-vnylcarbamoyll-propyl)-(S)- carbamic acid tert-butyl ester
  • the vessel was then flushed with argon and sealed and the resulting mixture stirred at 120°C for 24 h.
  • the resulting mixture was then washed with water (25 mL) and extracted with ethyl acetate.
  • the organic layer was dried with Na2S0 4 , filtered, and concentrated in vacuo.
  • the resulting residue was purified by RPHPLC (gradient 35-90, acetonitrile-water) to yield (1 - ⁇ 3-[5-(3,4-dimethoxy-phenoxy)- 1 H-indol-2-yl]-propylcarbamoyl ⁇ -propyl)-(S)-carbamic acid tert-butyl ester.
  • Test compounds were assessed for DPP-1 (Cathepsin C) inhibitory activity using a fluorogenic substrate, GR-AMC (Glycine-Arginine- amino-4- methylcoumarin, Bachem, 1-1215). The amount of amino-methylcoumarin released is proportional to the DPP-1 activity, and the reaction is monitored kinetically with a Molecular Devices plate reader using black 96-well plates. All compounds were tested under room temperature conditions.
  • the assay buffer consisted of 50 mM HEPES, pH 7.0, 100 mM NaCI, 2 mM glutathione (GSH), and 0.002% TWEEN 20. GSH and TWEEN 20 were added to the buffer fresh daily.
  • an in-house preparation of recombinant human DPP-1 (240 ⁇ stock, MW 49.6 kD) was diluted 600-fold in assay buffer containing fresh 2 mM dithiothreitol (DTT) to activate the enzyme, then diluted into assay buffer (without DTT) 133-fold for a DPP-1 working solution of 3 nM.
  • Test compounds were diluted in DMSO for 20x their final assay concentrations.
  • 100 mg of the Compound #2, prepared as in Example 6 is formulated with sufficient finely divided lactose to provide a total amount of 580 to 590 mg to fill a size O hard gel capsule.

Abstract

La présente invention concerne de nouveaux dérivés bicycliques, des compositions pharmaceutiques les contenant et leur utilisation dans le traitement de troubles et d'affections modulés par la DPP-1.
PCT/US2010/060986 2009-12-18 2010-12-17 Dérivés bicycliques utiles comme inhibiteurs de dpp-1 WO2011075634A1 (fr)

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AU2010330792A AU2010330792B2 (en) 2009-12-18 2010-12-17 Bicyclic derivatives useful as inhibitors of DPP-1
CN201080064075.6A CN102753524B (zh) 2009-12-18 2010-12-17 可用作dpp-1抑制剂的双环衍生物
ES10798434.6T ES2573698T3 (es) 2009-12-18 2010-12-17 Derivados bicíclicos útiles como inhibidores de DPP-1
EP10798434.6A EP2513054B1 (fr) 2009-12-18 2010-12-17 Dérivés bicycliques en tant qu'inhibiteurs de dpp-1
JP2012544881A JP5908410B2 (ja) 2009-12-18 2010-12-17 Ｄｐｐ−１の阻害剤として有用な二環式誘導体

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WO2012170867A1 (fr) * 2011-06-09 2012-12-13 Rhizen Pharmaceuticals Sa Nouveaux composes utilises comme modulateurs de gpr-119
JP2013514990A (ja) * 2009-12-18 2013-05-02 ヤンセン ファーマシューティカ エヌ．ベー． Ｄｐｐ−１の阻害剤として有用な置換ベンゾチアゾール誘導体及び置換ベンゾオキサゾール誘導体

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KR102581373B1 (ko) * 2013-07-03 2023-09-20 카리오팜 쎄라퓨틱스, 인코포레이티드 치환된 벤조퓨라닐 및 벤즈옥사졸릴 화합물 및 이의 용도
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JP2013514990A (ja) * 2009-12-18 2013-05-02 ヤンセン ファーマシューティカ エヌ．ベー． Ｄｐｐ−１の阻害剤として有用な置換ベンゾチアゾール誘導体及び置換ベンゾオキサゾール誘導体
WO2012119941A1 (fr) 2011-03-04 2012-09-13 Prozymex A/S Composés de peptidylnitrile à titre d'inhibiteurs de peptidases
WO2012170867A1 (fr) * 2011-06-09 2012-12-13 Rhizen Pharmaceuticals Sa Nouveaux composes utilises comme modulateurs de gpr-119
US20130045986A1 (en) * 2011-06-09 2013-02-21 Rhizen Pharmaceuticals Sa Novel compounds as modulators of gpr-119
JP2014524898A (ja) * 2011-06-09 2014-09-25 ライゼン・ファーマシューティカルズ・エスアー Ｇｐｒ−１１９のモジュレータとしての新規化合物
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AU2012267556B2 (en) * 2011-06-09 2017-04-13 Rhizen Pharmaceuticals Sa Novel compounds as modulators of GPR-119
AU2012267556B9 (en) * 2011-06-09 2017-05-11 Rhizen Pharmaceuticals Sa Novel compounds as modulators of GPR-119
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AU2010330792B2 (en) 2015-10-08
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